Summary. The stress response, though essential for survival, can become dysregulated, resulting in disease. Hyperactivity of the hypothalamic pituitary adrenal (HPA) axis characterizes a variety of illnesses including alcohol use disorder (AUD), drug abuse, depression, Alzheimer?s and Parkinson?s diseases, among others. This Phase I SBIR proposes a novel strategy aimed at normalizing pathologic HPA hyperactivity. Therapeutic attempts to use glucocorticoid receptor (GR) antagonists have shown some promise in conditions like AUD and depression. However, chronically blocking GR-mediated effects may be counterproductive as, for instance, it interferes with glucocorticoid negative feedback, leading to increased cortisol levels and mineralocorticoid receptor activation. CRF receptor type 1 (CRF1) antagonists have also been extensively explored, but thus far have proven disappointing, possibly because of the pharmacodynamics/pharmacokinetics properties of the existing drugs. Therefore, the identification of novel therapeutics to normalize hyperactivity of the HPA axis represents an area of significant unmet medical need. HPA hyperactivity is characterized by higher production of corticotropin-releasing factor (CRF) and glucocorticoids. Prolonged exposure to elevated glucocorticoids has been proposed to act on the central nervous system, causing hippocampal and prefrontal cortex functional impairments. In turn, it is believed that reduced hippocampal inhibition of the hypothalamus further promotes HPA axis hyperactivity. The present project will lay the foundations for the clinical development of a first-in-class therapeutic for multiple conditions characterized by HPA axis hyperactivity including AUD, depression and neurodegenerative diseases.